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1973 41: 369-377

Relation Between Bleeding Time and Platelet Connective Tissue Reaction After Aspirin
J. Hirsh, D. Street, J. F. Cade and H. Amy

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Relation

Between Tissue

Bleeding Reaction
D. Street,

Time

and

Platelet Aspirin
and H. Amy

Connective

After
J. F. Cade,

By J. Hirsh,

Aspirin prolongs the bleeding time in normal subjects and inhibits platelet release and aggregation with connective tissue and other biological agents. We have investigated one of the possible mechanisms by which aspirin prolongs the bleeding time by comparing the effects of aspirin and placebo on the bleeding time and platelet aggregation with connective tissue in normal volunteers. Two separate studies were performed. Both showed prolongation of the bleeding time and inhibition of the platelet connective tissue reaction after aspirin, but only the second study showed a significant correlation between these changes.

Both studies are reported in detail because the discrepancy between them illustrates some important principles that require consideration when relating the effects of drugs on platelet function in vitro to their effects in vivo. The findings suggest that when particular care is taken to standardize the measurement of the platelet connective tissue reaction in terms of the stimulus used, subject variability, and analysis of results, the prolonged bleeding time after aspirin can be shown to be related to the defect produced in the platelet connective tissue reaction.

T

HE INTERACTION diphosphate (ADP),3’5 in hemostatic aspirin,”3 tissue wave effects are have

OF plug

PLATELETS and thrombin6’7 formation. been shown to

with connective tissue, ‘ adenosine is thought to be of fundamental imA number decrease of antiinflammatory platelet aggregation drugs, with the of

portance including connective secondary These

and with low of aggregation thought to

concentrations with ADP’2’4 be due to

of thrombin’#{176} and to inhibit and with epinephrine.#{176}’2’3 by aspirin of release

inhibition

ADP from plasma and hemostasis

platelets.8.’#{176}’2 Aspirin has been shown to platelet proteins,17 and it has been suggested may be related to this acetylation reaction.’8

acetylate numerous that its effect on Aspirin has also been be have

been reported to increase the bleeding time in some as well as in patients with an underlying hemostatic suggested responsible that for the the defect prolongation in ADP of release bleeding produced time.15’2’

normal subjects,”’2”22 defect.2124 It has by However, aspirin others may

From ments of Submitted Supported Ontario

the

Department and
6,

of
1972;

Laboratory revised from July

Medicine, McMaster
10, 1972;

St. University,

Joseph’s Hamilton,

Hospital, Ontario, 17, of August Council of Pathology University

and 1972. Canada and

the Canada.

Depart-

Pathology March in Heart M.D., University, part

Medicine, grants

accepted Research

by

the

Medical Departments

and Medicine,

the

Foundation.

J.
McMaster and

Hirsh, St. Joseph’s

F.R.A.C.P.:
and St. Assistant Ontario, St. & Stratton, Director Hamilton, Joseph’s Hospital,

Professor, of Ontario, Hospital, Canada. Joseph’s Inc.

Hematology, Canada. Hamilton,

McMaster

Medical Technical Pathology,

Centre Assistant,

D. Street,
Ontario, of Medicine Chief Ontario,

B.Sc.:
Canada. and

Hematology

Laboratory,

J. F. Cade,
Technologist,

M.D.,

Ph.D.,
University, Hematology

M.R.A.C.P.:
Hamilton,

Professor,

Departments

McMaster

H.
Hospital,

Amy,

M.Sc.:

Medical Canada.

Laboratory, by Grune

Hamilton,

©
Blood,

1973

Vol. 41, No. 3 (March),

1973

369

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370 suggested effect We on have that the aspirin vessel investigated by aspirin, aggregation were performed, second. function in the in results platelet wall may itself the have
22.25,26

H1RSH ET AL an additional effect on hemostasis of the through bleeding to the Two an time changes separate that the tests in vitro were disto

mechanism

of prolongation changes tissue are of the in bleeding in normal described difficulties

produced in platelet studies corrected crepancy assess

by relating the with connective the Both in vivo. MATERIALS illustrates first some studies

time subjects.

having

a number

of shortcomings in detail in using because

AND

METHODS

Design
Study domized, Tests group
18

of Studies
I :

Forty performed in
12

normal design. before the of

subjects Twenty treatment

(all

young were in 48
(Ii

adult given subjects,
24

females) placebo after

were and 2 hr
20

studied were five group were in
24

using given of and studied the

a

ran-

double-blind were and

aspirin. placebo

all after hr (in

(in

treatment and

group), after

hr

(in
of
3 2

18

of the
placebo

placebo

group
in

and
five using after testing.

in
of a

of Study

the
2:

treatment

group),

four

the

the

treatment

group).
Thirteen double-blind

The
normal

study
cross-over

was
subjects

completed
males All design.

within
and subjects

mo.
females) were tested the hr morning before

randomized,

a light fat-free breakfast, and smoking The subjects were randomly allocated
later of Bleeding the aspirin treatments to times wear and hr after tissue all the of subjects period
24

were off in platelet

crossed those treatment. suspension agreed of

over. subjects aggregation The

was prohibited for at least into initial aspirin or placebo A period of 1 wk was selected
who study that not to was take No given were tests was frozen any subject in a given with completed in other had single aliquots medication a dose history as aspirin connective within and first

groups, to allow
and
2

and 1 wk the effects
second. performed

placebo were

tissue

before
batch before In before 300-mg

and
of

wk
thawed for of the

using

a single

connective

immediately at active least a week Four treatment

use. both studies and tablets during

the acid

study. were

bleeding.

acetylsalicylic

and

four

300-mg

tablets

of sodium

bicarbonate

were

given

as the

placebo.

Platelet
Blood
syringe parts
10

Studies
was
and of blood at room into blood plasma, platelet-rich a count using of

collected
a 19-gauge to one temperature plastic was

in plastic
needle. part tubes, centrifuged which plasma 200,000/cu a Payton was was of to

tubes
The obtain and at adjusted mm. an decanted

containing
blood was The aliquot 2000 by Platelet was

3.8%

trisodium with was The for citrate

citrate in a centrifuged platelet-rich platelet

using ratio at

a of 300 plasma

plastic nine

mixed blood plasma. retained

anticoagulant. platelet-rich

g for
was The

mm

dispensed remaining platelet-poor of to the obtain

counting.

g for
into dilution

15
separate

mm
with

at
plastic

room

temperature
The platelet-poor by platelet

to

obtain
count plasma

tubes. measured

autologous was

aggregation

a turbidimetric

method,27’28

aggregometer.

Bleeding

Time

In the first study, the bleeding time was performed by a modified Ivy method. The tourniquet was inflated to 40 mm Hg, and three incisions (3 mm long and 3 mm deep) were made on the volar aspect of the forearm. The bleeding time was taken as the
mean In described
(9

of the

the by long

three Mielke and

individual study, et 1 mm the al.2’

measurements. bleeding time was performed by the template method as

second

mm

time

was

taken

as the

deep) mean

The tourniquet was inflated to 40 mm were made on the volar aspect of the of the two individual measurements.

Hg, and forearm.

two
The

incisions
bleeding

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BLEEDING Preparation
Connective
semimicro Five The grams suspension

TIME AND PLATELET of Connective
tissue
container of connective was

CONNECTIVE Suspension
was
the were at
1740

TISSUE

371

Tissue
Chemical)
contained tissue

(Sigma
that

homogenized
assembly in
15 85

in
in ml

a Waring
an of ice-filled
0.9%

Blendor
cooling saline supernatant for

using
jacket. 30 mm. material

a

blending homogenized g

centrifuged

for
the

mm

at

4#{176}C, and

the

was
use. for not

aspirated,
The a period in the of study,

divided
at least and

into

aliquots,
activity when of

stored
of tcsted suspension

at
in

-20#{176}C,

and
tissue dilutions prepared

thawed
suspension in

immediately
remained four normal

before
stable controls

platelet-aggregating new

connective serial were

a month batches

monthly.

Assessment
In produced who maximum optical (percentage tissue of the paring and aspirin the placebo In the the were the first between not

of Platelet
study,
30%

Aggregation
collagen and study.
50%

and

Analysis
used aggregation in was as

of
each in

Results
experiment the same by for the (reaction were group tissue expressed and platelet-poor the of curve the time). at Serial connective of was as a two of each addition time). analyzed with was control the measuring: difference determination of connective The by those effects comin by for tissue dilutions that which subjects
(1)

the the in

concentration maximum units, and the time Platelet aggregation expressed

in

assessed a percentage plasma between

the in

change density the and

optical and of on values

density platelet-rich
(2)

between aggregation), beginning placebo

platelet-poor in seconds of in with optical
(2)

the the of

upward platelet these

deflection connective measurements

the the

curve reaction

tissue

absolute group. second
(1)

treatment

study, the in maximum optical

platelet change density time upward in

aggregation in between seconds deflection

connective units, slope the addition (reaction

assessed percentage plasma its steepest

measuring:

density platelet-rich the curve

of
each point and

difference determination (slope), and

(percentage
(3)

aggregation), of

the the

between the

the

beginning

of

of connective tissue were prepared, and each sample of platelet-rich plasma was tested at at least five dilutions of connective tissue to obtain a percentage aggregation over a range from greater than 75% to less than 25% on each occasion (Fig. 1). The effects of
aspirin the percentage and change placebo in aggregation, on the platelet of slope, and connective connective reaction tissue tissue time that as reaction was in and the so were required pretreatment analyzed to by produce sample.
100%

calculating the activity, as the shown and change a 1:2 same Thus, a in

concentration

the
1 :2

concentrated
dilution
1, 50%

connective
activity,

tissue
a 1 :4 dilution
(7%

suspension
25%

was
activity,
75% 75%

considered
on. aggregation aggregation
+43%.

to
For

have
after after

example, placebo aspirin,

Fig. dilution in

if a 1 :14
(50%

dilution
activity) of

activity)
required tissue aspirin 0.5, to

produced produce would placebo to 0.25 (Fig. be

was connective

concentration time tissue 2),
4).

The
then
75%,

results
against and time
50%,

of
25% of

the
the 60

change
change aggregation and 90

in
in sec

bleeding connective (Fig. (Fig.

produced
of
1,

by
0.75,

or
required

were produce 3), and

plotted

concentration

a slope

and

a reaction

RESULTS Study The

:r
results of the first study are summarized in Table
1.

There

was

no

significant either of the placebo change at tissue bleeding longation

difference the two and
2, 24,

in the pretreatment indices of the platelet groups. hr in aspirin At
24

values for connective

the bleeding time or for tissue reaction between was no significant platelet connective increase in the proso that

aspirin or 48 In the

the

In the placebo group, there bleeding time or in the there four there was a significant

reaction.

group, hr, but

time at 2 hr. of the bleeding

time,

subjects showed a considerable was wide individual variation

From bloodjournal.hematologylibrary.org by guest on October 28, 2011. For personal use only.

372

HIRSH

ET AL.

Sc

_si ---Aftbo

7’

44----

-

3-

so

(2
2O

30

4)

10 0I 01

140 130
lx

0-7
05 05 04 03 n0 4)0

02

60 Sc 01
46

kG.
81012leli2O2530?0 24

AG.

i
WTi0N

W0N

Fig. 1. Platelet reaction before and after placebo expressed as percentage and slope (left).

to increasing dilution of connective tissue (collagen) or aspirin in subject A.G. Platelet reaction has been aggregation (top right), reaction time (bottom right),

50

80
-

.r.0/P-0o1

40
C

20

2

4

6

A
40

Biseding

Isne

8 (mon.)

10

12

#{149}#{149} - -

r.O55/P#{128}oo

Fig. 2. Relation between change in bleeding time and change in collagen concentration (#{176}/o) required to produce aggregation of 75#{176}/o (top), 50#{176}/o (middle), and 25#{176}/o (bottom) after placebo (closed circles) and aspirin (open circles). NS, not significant, r, correlation coefficient.

4)

A

4 Bleeding Time

8 (mm.)

0

12

4

r.O12/N5

4

6

8 Tims (mm.)

10

12

A

Bisiding

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BLEEDING

TIME AND PLATELET

CONNECTIVE

TISSUE
80

373

1

h
. #{149}

r.085/PoGoi

,2

A4BI.edeng

aTime

(mill)

a

12

-

...-.-.. -r.O42
NS

4

‘20 (.2

1

#{149}

a
#{149} 2
A4Bleedlng8Time (mm.) 12

#{176}i

I
Fig. 3. Relation between change in
#{149}i
A4nTimSmIn) 12

bleeding time and change in collagen concentration (#{176}/o) required to produce a slope of 1.00 (top), 0.75 (second from top), 0.50 (second from bottom), and 0.25 (bottom) after placebo (closed circles) and aspirin (open circles). NS, not significant; r, correlation coefficient.

t!.
#{149}rr2 I

4

8 Bleeding Time

8 (mm.)

10

12

A

50

40

30 0
-

r-O’Ol/NS

10

0

ABleedlngTine(mln.) I

a

2

30

20 0 0 0 0 2 0 r-O’lO/NS

Ic

0

A

Bleeding

a Tim.

(mm.)

a

10

12

Fig. 4. Relation between change in bleeding time and change in collagen concentration (#{176}Io) required to produce a reaction time of 60 sec (top) and 90 sec (bottom) after placebo (closed circles) and aspirin (open circles). NS, not significant; r, correlation coefficient.

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374 Table 1. Bleeding
After

HIRSH Time and Platelet
Aspirin

ET AL.

Connective
(Study

Tissue
1)

Reaction

and Placebo

Placebo
Test Pre 2 24 48 Pre 2

As pirin
24 48

Bleed ing time (mm) Aggregation
(#{176}/o)

Reaction

time

(sec)

4.08 (0.03) 46.5 (3.27) 63 (4.1)

5.00 (0.00) 46.0 (4.32) 69 (3.6)

4.25 (0.35) 41.4 (2.92) 64 (3.0)

3.50 (0.00) 35.3 (9.82) 61 (6.7)

4.61 (0.29) 42.0 (2.32) 58 (3.9)

775* (1.03) 23.7
(4.00)

6.83 (1.27)

16.9t
(2.64) 79* (6.7) treatment (paired

73t (10.3)

4.33 (0.14) 14.01 (3.78) 63 (7.6) with t test),

Pre, 2, 24, and 48 refer either aspirin or placebo. 4Value after treatment tp
tP <0.001.

to measurements before and 2, 24, and 48 hr after Values are mean, with standard error in parentheses. significantly different from that before treatment

<0.001,

tp <0.05.

the
time in

over-all
in

difference five subjects of the

was platelet

not tested

statistically was normal. connective at 48 hr.

significant. There tissue was reaction the

At

48

hr, 2 and

the 24

bleeding decrease hr and

the

a significant at

both There time

indices percentage

in the ing

aggregation

was no significant at 24 hr and the by either index.

correlation between inhibition of the platelet In fact, the three

prolongation connective

tissue subjects

of the bleedreaction as with the

assessed greatest
prolongation
longation

aspirin-treated tissue reaction the subject with the least decrease

decrease in the platelet connective of the bleeding time, whereas of the bleeding time showed tissue reaction.

showed the least the greatest proin the platelet

connective Study The showed platelet
2

results

of

the

second

study

are

summarized

in

Table and after the

2. All impairment aspirin,

subjects but of the there

a significant connective

prolongation tissue reaction in the

of the bleeding time for all three indices bleeding between connective aggregation a significant in connective of the
0.75, 0.5,

was no significant change tissue reaction after placebo. There was a significant after aspirin and
75%

time

or the tissue

in

platelet in

connective bleeding time required maximum between the 3). There

correlation in the
maximum

increase but not correlation tissue and
0.25

the and 2).

increase
50%

concentration
25%

to produce aggregation increase required was no increase

(Fig. in bleeding to produce significant in connective reaction

There time a slope and

was the

also increase not

concentration (Fig. time either and the a 60-sec

of 1 but between concentration 4).

correlation tissue time (Fig.

increase required

in bleeding to produce

or a 90-sec

DISCUSSION The findings in both studies confirm other reports that aspirin prolongs the

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BLEEDING

TIME AND PLATELET
2. Changes in Bleeding

CONNECTIVE
Time

TISSUE
Connective Tissue Reaction

375

Table

and Platelet

After Aspirin
Test

and Placebo

(Study 2)
Aspirin p

Placebo

Bleeding Aggregation 75 50 25

time

(mm) (#{176}/o)

+0.01 (1.08) -0.31 (3.84) -0.54 (4.16) -1.15 (3.44)

+4.09 (2.83) +40.58 (18.59) +22.08 (13.33) +12.77 (10.80) +22.38 (15.26) +15.38 (9.64) +12.31 (8.35)

<0.001

<0.001 <0.001 <0.005

Slope 1.00
0.75 0.50

+0.77
(2.74) +0.23 (1.64) -0.31 (1.70)

<0.001
<0.001 <0.001 <0.001

0.25 Reaction 60 90 time (sec)

-0.33
(1.61)

+10.27
(6.34) +21.00

-0.31 (3.15) -0.25 (1.86) deviation
the changes per cent aggregation, and compares change

<0.005
<0.005

(14.31)
+11.08

(8.69) in parentheses.
are in the concentration of conslope, and reaction times shown. after placebo with change after

Values are mean changes, with standard For platelet connective tissue reaction,
nective tissue p is derived required to produce from paired t test

aspirin.

bleeding
tissue

time in normal subjects”2’22 reaction.”3 In addition, the in bleeding produced

second

and inhibits the study demonstrates the suppression when this or of
it was

platelet connective a direct correlatter Such sought hemostasis of the platelet reaction is a correlation or because, can be

lation between the increase connective tissue reaction expressed in terms

time and by aspirin, because were as changes function, if (1) vitro

of percentage

aggregation either methods drugs such

slope. not

has not hitherto been described, as in our first study, less precise The mechanism by correlating in a test of several which examined by with changes However, is only strength stimulus and (4) than may the also one of

used. impair in the such result of in vitro as the bleeding, stimulus
(2)

aspirin

drug-induced of hemostatic could factors be in obscured the in relevant

tests time.

a correlation stimulus

the

being if an strength

examined of the

to hemostasis, tests, (3)

inappropriate

is used

if the

used for the in vitro test if the subject’s response drug be being important tested. in The the

varies during the course of the investigation, to the stimulus is affected by factors other pharmacologic suppression of thrombosis, of platelet and function that it is likely

treatment

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376 these effects The the the
function

HIRSH considerations of drugs discrepancy that of are also relevant platelet our two to platelet
(1) A

ET AL

in the

assessment

of the because in The

antithrombotic
it illustrates

suppress between the general in vitro

function. studies is of interest outlined function number of the resulted of above in vivo. different

importance following

principles

relating first connective

platelet study had tissue

as assessed

shortcomings. the in

suspensions from the connective

were used over same dried extract. tissue reaction

3 mo

This the

study, although in wide variation group, despite was standardized the 3 mo of

all were prepared in the platelet the fact that the against the study. platelets (2) The of stimulus tissue

placebo stimulus throughout

strength of the from the same
connective tissue

connective tissue control subjects
reaction was

examined two indices and with blurred Ivy the

using of

only the

one platelet

strength

and

was

analyzed (3) drug time sensitive study.

using

only

connective

reaction. randomized, Thus, bleeding and second less the

The effects double-blind effect was may performed to aspirin

of aspirin design but have been by than the

placebo different by method,

were compared using a subjects in each group. variations. is less method used (4) reproducible in the The which

individual template

modified

In the second as far as possible. of connective rigidly standardized preparation during of variation of his own control. carefully variation. correlation

study, an attempt Thus, the effect tissue concentrations, by using the study, response Variation

was made to minimize of the stimulus was and the strength of aliquots was limited were within

these sources examined over of the stimulus connective period. The by was

of error a range was tissue effects as by

frozen which

the same to a 2-wk minimized subjects

between of the factors when between

subjects response

using each minimized

standardizing It was only was found

such these the

as diet, variables effect of

exercise, were aspirin n

smoking, controlled the bleeding

and diurnal that a direct time and

the platelet connective tissue reaction and then only when a relatively strong stimulus was used. The results of our second study, therefore, support the hypothesis that the prolongation in the bleeding time produced by aspirin is causally related to suppression of the platelet connective tissue reaction. REFERENCES
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8.

T1ME AND PLATELET
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